Glutamic acid is the major excitatory neurotransmitter in the central nervous system and it is widely accepted that anomaly of its control is involved in creation of pathological conditions of progressive encephalopathies such as disorder in memory, ischemic encephalopathy, amyotropic lateral sclerosis (ALS), Parkinson's disease, and Huntingon's chorea (Meldrum, B. S., Meruolgy, 1994 November;44 (11 Supple 8):S14–23; Nishizawa, Y., Life Sci. 2001, Jun. 15;69(4):369–81). This led to many studies on glutamic acid receptors throughout the cranial nerves, resulting in discovery of many types of receptors (three ionic type receptors and eight metabolic type receptors) in the central nervous system. With a view to developing therapeutic medicines for the above-mentioned diseases, even now development of agonists specific to such receptors is being energetically made (for details, reference is made to Barnard, E. A., Trends Pharmacol. Sci., 1997, May; 18(5):141–8; Schoepp, D. D., Conn, P. J., Trends Pharmacol. Sci. 1993 January; 14(1):13–20).
On the other hand, there are few studies on glutamic acid receptors other than in central nervous system. Glutamic acid is known to serve also as an energy source and a source for trapping ammonia that is no longer necessary and always exist in blood plasma in an amount on the order of several tens micromoles or more. In the central nervous system, the concentration of intracellular glutamic acid is on the order of nanomoles or less due to the existence of blood-brain barrier. As a result, the affinity of the above-mentioned glutamic acid receptor discovered in the central nervous system for glutamic acid is on the order of nanomoles to micromoles, so that the glutamic acid receptor can act only when glutamic acid is released from the nerve ending. In addition, the glutamic acid receptor tends to be inactivated or cause tachyphylaxis; in the central nervous system, gliacytes always take up glutamic acid through specific transporters to lower extracellular concentration of glutamic acid. On the other hand, in those sites other than the central nervous system where no protection by the blood-brain barrier is available, if glutamic acid receptors are expressed, it is considered that the glutamic acid receptors are always in a stimulated state and thus actually are inactivated and do not function.
However, in 2001, Chaudhari, N., Landin, A. M., Roper, S. D. et al. discovered low affinity glutamic acid receptor as an “umami” receptor from rat gustatory bud cells (Nat. Neurosci. 2000, February; 3(2):113–9). The umami receptor is gustatory type mGluR4, which has the same host gene as type 4 (mGluR4), a subtype of rat brain type metabotropic type glutamic acid receptor (Tanabe, Y. et al., Neuron, 1992, January;8)1):169–79; Flor, P. J. et al., Neuropharamacology, 1995, February;34(2):149–55) and is partially defective of extracellular domain of the brain type mGluR4 due to splicing mutation.
Today, we have several pieces of knowledge that suggest physiological functions of the peripheral glutamic acid receptor (Berk, M., Plein, H., Ferreira, D., Clin. Neuropharmacol., 2001, May-June;24(129–32; Karim, F., J. Neurosci. 2001, Jun. 1;21(11):3771–9; Berk, M., Plein, H., Belsham, B., Life Sci. 2000;66(25):2427–32; Carlton, S. M., Goggeshall, R. E., Brain Res. 1999, Feb. 27;820(1–2):63–70; Haxhij. M. A., Erokwu, B., Dreshaj, I. A., J. Auton. Nerv. Syst. 1997, Dec. 11;67(3):192–9; Inagaki, N., FASEB J. 1995, May;9(8):686–91; Erdo, S. L., Trends Pharamcol. Sci., 1991, November;12(11):426–9; Aas, P., Tanso, R., Fonnum, F., Eur. J. Pharamacol. 1989, May 2;164(1):93–102; Said, S. I., Dey, R. D., Dickman, K., Trends Pharmacol. Sci. 2001, July;22(7):344–5; Skerry, T. M., Genever, P. G., Trends Pharamacol., Sci. 2001, April;22(4):174–81).
Incidentally, for mammals including humans to make normal growth and maintain normal (healthy) life, it is necessary to orally take up necessary amounts of nutrients at necessary timing and excrete unnecessary matter. This is actually done by a digestive tract, which is a single tube consisting of oral cavity, stomach, small intestine and large intestine. The process of digestion and absorption is controlled by intrinsic intestinal neuroplexus and extrinsic cranial nerves. The judgment at to whether or not to take a necessary nutrient is performed by integration in the brain of a pathway that the individual is aware of (taste) with an autonomous pathway that the individual is unaware of (visceral sense). It is considered that salty taste (sodium, potassium, etc.) serves as a marker of minerals and is useful for maintaining the osmotic pressure of the body fluid; the sweetness (glucose) serves as a marker of carbohydrates and is useful for supplementing energy; umami (sodium glutamate) serves as a marker of protein source and is useful for supplementing energy and body protein; and bitterness serves as a marker of toxic substances. That is, necessary nutrients are taken up relying on the tastes thereof. Then, if the necessary amounts are fully taken up is judged based on satiety that is obtained through a series of intracerebral processes of signal input to nucleus solitary tract from the afferent pathway of activated vagus nerve through nutrient sensors existing in the stomach, small intestine, and liver-portal vein (Bray, G. A., Proc. Nutr. Soc., 2000;59:373–84; Bray G. A., Med. Clin. North. Am. 1989:73:29). In addition, it is considered that digestion and absorption (secretion of digestive enzymes, enterokinesis, etc.) are controlled through efferent pathway of the vagus nerve. However, details of the mechanism are unclear. Then, finally satiety is obtained and eating behavior is terminated. In case of eating a substance toxic to the organism (poison), it is considered to be discharged by vomiting or diarrhea through humoral and neural responses. In this case too, details of the mechanism are unclear.
On the other hand, physiological studies on the mechanism of chemical sense in the digestive tract have been performed since a long time ago and it is supposed that there is a sensor that senses the content in the digestive tract (for the details, reference is made to Mei, N., J. Auton. Nerv. Syst., 1983;9:199–206; Mei, N., Lucchini, S., J. Auton, Nerv. Syst., 1992;41:15–8). The digestive sensors include a glucose sensor (Mei, N., J. Physiol. (Lond.) 1978, 282, 485-5–6), a temperature sensor (El Ouazzani, T., Mei, N., Exp. Brain Res. 1979;15;34:419–34), an osmotic pressure sensor (Mei, N., Garnier, L., J. Auton. Nerv. Syst., 1986;16:159–70), a pH sensor, an amino acid sensor (Mei, N., Physiol. Rev., 1985;65:211–37), and a pressure sensor (Barber, W. D., Burks, T. F., Gastroenterol Clin. North. Am. 1987; 16:521–4).
In particular, the sensor that recognizes glutamic acid was suggested by Niijima et al. from neural excitation that occurred when glutamic acid was administered in the digestive tract by using the technique of electrically grasping the neural activity in the stomach branch and abdominal cavity branch of the vagus nerve that controls mainly the stomach and small intestine, assuming that there is a mechanism that recognizes glutamic acid in the vagus nerve ending (Niijima, A., Physiol. Behav., 1991;49:1025–8).